Unchecked inflammation in the brain results in neural tissue necrosis which can manifest as seizures, dementia, loss of mental capacities, or death. For example, epilepsy, dementia due to Alzheimer""s disease, stroke and traumatic brain injury have all been linked to dysfunctional inflammatory responses, although causal relationships between agents responsible for inducing the inflammatory response and the inflammatory response thereby induced have been speculative.
With regard to Alzheimer""s disease, one agent, the secreted amyloid precursor protein (sAPP) has been shown to be neuroprotective, (Mattson et al., 10 Neuron 243 (1993) and Smith-Swintosky et al., 63 J Neurochem 781 (1994) and the regulator ApoE has been shown to potentiate the neuroprotective activity of sAPPxcex1. Barger and Mattson, 69(1) J Neurochem 60 (1997). The extent of neuroprotection was shown in Barger and Mattson to vary among allelic variants of apolipoprotein E (ApoE), with ApoE3 apparently being superior to ApoE4 in its ability to induce the neuroprotective effects. ibid. It was speculated in Barger and Mattson that individuals who carried at least one ApoE4 allele had reduced sAPP-related neuroprotection, due to ineffectual inhibition of phosphoinositides, and resulting detrimental calcium ion increases. Furukawa et al., 67 J Neurochem 1882 (1996), showed the neuroprotection to result from residues 596-612, the existence of these residues in sAPPxcex1 distinguish sAPPxcex1 from sAPPxcex2.
Alzheimer""s disease currently affects 4 million Americans. The cumulative health care costs associated with Alzheimer""s, stroke and traumatic brain injury are $155 billion/year in the United States. Americans desperately need treatments which ameliorate the symptoms of these diseases and injuries.
Citation of the above documents is not intended as an admission that any of the foregoing is pertinent prior art. All statements as to the date or representation as to the contents of these documents is based on subjective characterization of information available to the applicant, and does not constitute any admission as to the accuracy of the dates or contents of these documents.
It is therefore an object of the present invention to provide materials useful in assays for agents to treat inflammation related to sAPP.
It is a further object to provide methods to reduce the negative inflammatory effects of sAPP.
It is yet another object to provide methods to potentiate the positive neuroprotective effects of sAPPxcex1 by inhibiting the inflammatory effects of that molecule.
It is yet another object to provide research materials and methods useful to study sAPP.